Volume 35, Issue 1

The analysis of blood cell count including differential, is the most frequent laboratory test and has still essential diagnostic value in the diagnosis of primary or secondary diseases of the hematopoietic system. The interpretation is based on a comparison with age matched reference intervals, despite the fact that a comparison with the patients own preceding values allows a more precise statement. In the present study, blood counts and differential were performed in 1158 healthy males and females with an age ranging from 16 to 75 years were investigated using current hematology systems. The donors were examined by personnel physicians and those examining blood donors in transfusion medicine and in addition were asked via standardized questionnaire. The study resulted in reference ranges for the complete blood count, the differential blood count and reticulocytes. For several analytes, age-, gender- or analyzerspecific reference ranges were obtained. We found an age dependent decrease of the erythrocyte concentration and an increase for MCH and MCV as well as for basophils. These findings could be important for the dignosis of diseases of the elderly like myeloproliferative diseases (MPN) and myelodysplasias (MDS). Gender specific changes could be shown for the hemoglobulin-, the erythrocyte- and reticulocyte concentration, as well as for hematocrit and MCHC, being reduced in females. On the other hand, females showed significant higher levels for platelets and leukocytes, based on an increase of neutrophils and lymphocytes. The leukocytosis of smokers was confirmed for neutrophils and lymphocytes but lower than one could expect from recent studies. A multicentric study shows a broader distribution compared to unicentric data but this probably better reflects the reality and improves the applicability of the reference ranges.

The analysis of blood cell count including differential, is the most frequent laboratory test and has still essential diagnostic value in the diagnosis of primary or secondary diseases of the hematopoietic system. The interpretation is based on a comparison with age matched reference intervals, despite the fact that a comparison with the patients own preceding values allows a more precise statement. In the present study, blood counts and differential were performed in 1158 healthy males and females with an age ranging from 16 to 75 years were investigated using current hematology systems. The donors were examined by personnel physicians and those examining blood donors in transfusion medicine and in addition were asked via standardized questionnaire. The study resulted in reference ranges for the complete blood count, the differential blood count and reticulocytes. For several analytes, age-, gender- or analyzerspecific reference ranges were obtained. We found an age dependent decrease of the erythrocyte concentration and an increase for MCH and MCV as well as for basophils. These findings could be important for the diagnosis of diseases of the elderly like like myeloproliferative diseases (MPN) and myelodysplasias (MDS). Gender specific changes could be shown for the hemoglobulin-, the erythrocyte- and reticulocyte concentration, as well as for hematocrit and MCHC, being reduced in females. On the other hand, females showed significant higher levels for platelets and leukocytes, based on an increase of neutrophils and lymphocytes. The leukocytosis of smokers was confirmed for neutrophils and lymphocytes but lower than one could expect from recent studies. A multicentric study shows a broader distribution compared to unicentric data but this probably better reflects the reality and improves the applicability of the reference ranges.

Male testosterone concentrations gained recent attention in the field of andrology. Various epidemiological cohort studies presented associations of low serum testosterone concentrations with incident cardiovascular risk factors and increased mortality risk. Furthermore, low serum testosterone concentrations are integral part for the diagnosis of late-onset hypogonadism. Because of their high validity and throughput, mass spectrometry assays have replaced conventional immunoassays for testosterone measurement, and are believed to become the “gold standard” for sex hormone quantitation. This article will focus on challenges in the measurement of serum testosterone concentrations and will provide practical information on the interpretation of serum testosterone measurements.

Male testosterone concentrations gained recent attention in the field of andrology. Various epidemiological cohort studies presented associations of low serum testosterone concentrations with incident cardiovascular risk factors and increased mortality risk. Furthermore, low serum testosterone concentrations are integral part for the diagnosis of late-onset hypogonadism. Because of their high validity and throughput, mass spectrometry assays have replaced conventional immunoassays for testosterone measurement, and are believed to become the "gold standard" for sex hormone quantitation. This article will focus on challenges in the measurement of serum testosterone concentrations and will provide practical information on the interpretation of serum testosterone measurements.

Costs for heparin-induced thrombocytopenia (HIT) should be considered for any assessment of the cost-effectiveness of a certain strategy of thrombosis prophylaxis in a hospital. Five recent studies analyzed the cost of HIT as primary outcome. These studies reported widely differing estimates for the costs of a HIT case, which might be largely related to the different methodological approaches. The most plausible HIT cost estimates range between €9,000 and €15,000 per case for European hospitals and US$30,000–45,000 per case for hospitals in the United States. The approximate threefold cost difference between Europe and the US is to some extent caused by the very different costs for certain interventions and treatments, i.e., they are dependent on the economic environment of the hospitals analyzed. Based on the assumption that clinical management of acute HIT does not differ substantially between different medical systems, we recently developed the HIT cost calculator (http://www.wi.hs-wismar.de/~ipam/html_neu/hittool.html) based on detailed analysis of additional resources required owing to the presence of HIT in 128 patients with clinical HIT. This tool offers interested hospitals a very transparent method to calculate their own HIT-related costs. Zusammenfassung Die Kosten für eine Heparin-induzierte Thrombozytopenie (HIT) sollten für die Ermittlung der Kosteneffizienz jeder Strategie einer Thromboseprophylaxe in Krankenhäusern untersucht werden. Aktuell wurden fünf Studien publiziert, die die HIT-assoziierten Kosten als primären Endpunkt untersucht haben. Diese Studien wiesen erhebliche Unterschiede der HIT-assoziierten Kosten pro Fall auf, welches überwiegend in den unterschiedlichen methodischen Ansätzen begründet ist. Die plausibelste Schätzung der HIT-Kosten geht von etwa 9.000 bis 15.000 € pro Fall in europäischen Krankenhäusern und 30.000 bis 45.000 US-Dollar pro Fall für Krankenhäuser in den USA aus. Die circa dreifach höheren Kosten in den USA sind teilweise durch die ausgesprochen unterschiedlichen Kosten für bestimmte Interventionen und Therapien begründet, d.h. sie sind abhängig von den wirtschaflichen Rahmenbedingungen der jeweiligen Krankenhäuser in den verschiedenen Ländern. Ausgehend von der Annahme, dass das klinische Management einer akuten HIT sich in den unterschiedlichen medizinischen Systemen nicht wesentlich unterscheidet, haben wir einen HIT-Kostenkalkulator entwickelt (http://www.wi.hs-wismar.de/~ipam/html_neu/hittool.html), der eine detaillierte Analyse der zusätzlichen Ressourcen pro HIT-Fall aus der Basis von 128 Patienten mit klinischer HIT erlaubt. Dieses Instrument erlaubt es interessierten Krankenhäusern, eine transparente Kalkulation der eigenen HIT-bezogenen Kosten durchzuführen.

Heparin-induced thrombocytopenia (HIT) is a clinical-pathological syndrome, i.e., criteria for diagnosis include a compatible clinical picture and laboratory detectability of heparin-dependent, platelet-activating antibodies of IgG class (“HIT antibodies”), and the lack of a more compelling alternative diagnosis. Heparin administration frequently leads to formation of antibodies of one or several immunoglobulin classes (IgG, IgA, IgM) that recognize a “self” protein, platelet factor 4 (PF4), when PF4 forms multimolecular complexes with heparin. A practical problem is that only a small minority of patients who form heparin-dependent antibodies also develop clinically evident HIT; serum from such patients typically contains IgG antibodies that are strongly platelet-activating. In addition, poorly characterized patient-dependent factors also influence risk of HIT, and thus even a strong positive in vitro test for HIT antibodies does not necessarily mean that HIT will occur. Given the possibility of non-HIT thrombocytopenia among heparin-treated patients, a positive test for heparin-dependent antibodies in such a patient might well lead to a false diagnosis of HIT. One scenario with considerable potential for “overdiagnosis” of HIT is the post-cardiac surgery patient in whom early postoperative thrombocytopenia and/or thrombosis of non-HIT etiology triggers testing for heparin-dependent antibodies a few days later. In this situation, “incidental” seroconversion, rather than confirmation of HIT, is a frequent outcome. This review summarizes the utility of Bayes' rule in making or refuting a diagnosis of HIT. Here, we suggest a pre-test odds of HIT (based on the clinical context) should be revised using the HIT antibody test result – including the strength of any positive result – through an appropriate likelihood ratio. This post-test odds of HIT yields a more reliable assessment of HIT status, potentially minimizing HIT overdiagnosis. Zusammenfassung Die Heparin-induzierte Thrombozytopenie (HIT) stellt ein klinisch-pathologisches Syndrom dar, dessen diagnostische Kriterien den Labornachweis Heparin-abhängiger, Thrombozyten-aktivierender IgG Antikörper (“HIT Antikörper”) bei einem vereinbaren klinischen Bild und den Ausschluss alternativer Diagnosen umfassen. Heparin führt häufig zur Bildung von Antikörpern einer oder mehrerer Immunglobulinklassen (IgG, IgA, IgM), die ein Autoantigen aus Plättchenfaktor 4 (PF4) in einem multimolekularen Komplex mit Heparin erkennen. Ein praktisches Problem resultiert aus der Tatsache, dass nur eine kleine Minderheit der Patienten mit Heparin-abhängigen Antikörpern auch eine klinisch relevante HIT entwickelt. Das Serum dieser Patienten enthält typischerweise stark Thrombozyten-aktivierende IgG Antikörper. Darüber hinaus beeinflussen bisher wenig charakterisierte Faktoren das Risiko eine HIT zu entwickeln. Aus diesem Grund tritt auch bei einem stark positiven In-vitro-HIT-Antikörpertest nicht notwendigerweise eine HIT auf. Unter Berücksichtigung der Möglichkeit einer Non-HIT-Thrombozytopenie bei Heparin-behandelten Patienten, könnte ein positiver HIT-Test für Heparin-abhängige Antikörper zu einer Fehldiagnose HIT führen. Herzchirurgische Patienten, bei denen häufiger eine frühe postoperative Thrombozytopenie und/oder Thrombose einer Non-HIT-Ätiologie auftritt, die wiederum eine folgende Untersuchung von Heparin-abhängigen Antikörpern auslöst, weisen ein erhebliches Potenzial für eine “Überdiagnostik” einer HIT auf. In dieser Situation ist eine “zufällige” Serokonversion und nicht einen Bestätigung einer tatsächlichen HIT ein häufiger Befund. In diesem Übersichtsartikel wird der Nutzen des Bayes' Wahrscheinlichkeitstheorems für die Diagnose oder den Ausschluss einer HIT dargestellt. Wir empfehlen die Berücksichtigung der Prä-Test-Wahrscheinlichkeit einer HIT (in Abhängigkeit vom klinischen Kontext) bei der Beurteilung des HIT-Antikörpertestergebnisses, einschließlich der Stärke jedes positiven Ergebnisses, über eine angemessene Wahrscheinlichkeitsrate. Mit Hilfe der Post-Test-Wahrscheinlichkeit einer HIT kann eine zuverlässigere Untersuchung des HIT-Status erfolgen, die die Überdiagnose einer HIT minimiert.

Following DIN EN ISO 15189 and the “Richtlinien der Bundesärztekammer zur Qualitätssicherung laboratoriumsmedizinischer Untersuchungen” pre-examination procedures have to be established in order to make results as comparable as possible. For standardization of the pre-examination variables the working group “Richtwerte” (guide values) of the DGKL proposes an exemplary standard operation procedure adjustable to local environments. Using the proposed standard operation procedure the estimation of reference intervals should lead to more valid and comparable results.